ORCID Profile
0000-0003-3400-5005
Current Organisation
University of Cambridge
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Publisher: The Endocrine Society
Date: 26-12-2017
Publisher: Springer International Publishing
Date: 2015
Publisher: Elsevier BV
Date: 07-2023
Publisher: Oxford University Press (OUP)
Date: 10-01-2012
Abstract: Oxidized cholesterol metabolites (oxysterols) promote inflammation in a variety of cell types and are thought to be involved in a number of disease pathologies. Oxysterol concentrations are increased in pregnancy, together with systemic oxidative stress and inflammation. We tested the hypothesis that oxysterols 25-hydroxycholesterol (25-OHC) and 7-ketocholesterol (7-ketoC) promote placental trophoblast inflammation, and determined the mechanisms involved. Treatment of primary trophoblasts in culture with 25-OHC and 7-ketoC increased the production of proinflammatory cytokines (interleukin-6, macrophage inflammatory protein-1β and tumour necrosis factor-α) in a concentration-dependent fashion. Inhibition of TLR4 activation using selective inhibitors of TLR4 complex formation (OxPAPC) or signalling transmission (CLI095) prevented lipopolysaccharide (LPS)- and oxysterol-induced inflammatory cytokine production. Pretreatment of trophoblasts with selective inhibitors of I-kB kinase activity (parthenolide and TPCA-1) reduced oxysterol- and LPS-stimulated inflammatory responses, consistent with the involvement of the nuclear factor kappa B (NF-κB) pathway downstream of TLR4 signalling. Both oxysterols also increased the phosphorylation and nuclear localization of NF-κB subunit p65/RelA. Oxysterols are also known to activate liver X receptors (LXRs) which can inhibit inflammatory signalling, either directly or indirectly via membrane cholesterol reduction. Treatment with the LXR agonist, T0901317, exerted significant anti-inflammatory effects, reducing LPS- and oxysterol-driven cytokine production. Treatment with methyl-β-cyclodextrin to deplete membrane microdomain cholesterol and thereby disrupt TLR4 signalling, similarly abrogated their effects. Together, these findings indicate that although oxysterols likely activate both pro- and anti-inflammatory pathways in the placenta, the predominant effect is the promotion of placental inflammation via TLR4-dependent activation of NF-κB.
Publisher: Elsevier BV
Date: 04-2013
DOI: 10.1016/J.CBI.2013.03.007
Abstract: The human placenta, in addition to its roles as a nutrient transfer and endocrine organ, functions as a selective barrier to protect the fetus against the harmful effects of exogenous and endogenous toxins. Members of the ATP-binding cassette (ABC) family of transport proteins limit the entry of xenobiotics into the fetal circulation via vectorial efflux from the placenta to the maternal circulation. Several members of the ABC family, including proteins from the ABCA, ABCB, ABCC and ABCG subfamilies, have been shown to be functional in the placenta with clinically significant roles in xenobiotic efflux. However, recent findings suggest that these transporters also protect placental tissue by preventing the cellular accumulation of cytotoxic compounds such as lipids, sterols and their derivatives. Such protective functions are likely to be particularly important in pregnancies complicated by inflammatory or oxidative stress, where the generation of toxic metabolites is enhanced. For ex le, ABC transporters have been shown to protect against the harmful effects of hypoxia and oxidative stress through increased expression and efflux of oxysterols and glutathione conjugated xenobiotics. However, this protective capacity may be diminished in response to the same stressors. Several studies in primary human trophoblast cells and animal models have demonstrated decreased expression and activity of placental ABC transporters with inflammatory, oxidative or metabolic stress. Several clinical studies in pregnancies complicated by inflammatory conditions such as preecl sia and gestational diabetes support these findings, although further studies are required to determine the clinical relevance of the relationships between placental ABC transporter expression and activity, and placental function in stressed pregnancies. Such studies are necessary to fully understand the consequences of pregnancy disorders on placental function and viability in order to optimise pregnancy care and maximise fetal growth and health.
Publisher: Elsevier BV
Date: 07-2015
Publisher: Elsevier BV
Date: 02-2014
DOI: 10.1016/J.PLACENTA.2013.11.010
Abstract: Workshops are an important part of the IFPA annual meeting as they allow for discussion of specialized topics. At IFPA meeting 2013 there were twelve themed workshops, four of which are summarized in this report. These workshops related to various aspects of placental biology but collectively covered areas of pregnancy pathologies and placental metabolism: 1) diabetes in pregnancy 2) lipids, fatty acids and the placenta 3) oxygen in placental development and pathologies 4) stem cells and pathologies.
Publisher: Elsevier BV
Date: 02-2018
DOI: 10.1016/J.AJOG.2017.12.002
Abstract: Fetal growth restriction is a major determinant of perinatal morbidity and mortality. Screening for fetal growth restriction is a key element of prenatal care but it is recognized to be problematic. Screening using clinical risk assessment and targeting ultrasound to high-risk women is the standard of care in the United States and United Kingdom, but the approach is known to have low sensitivity. Systematic reviews of randomized controlled trials do not demonstrate any benefit from universal ultrasound screening for fetal growth restriction in the third trimester, but the evidence base is not strong. Implementation of universal ultrasound screening in low-risk women in France failed to reduce the risk of complications among small-for-gestational-age infants but did appear to cause iatrogenic harm to false positives. One strategy to making progress is to improve screening by developing more sensitive and specific tests with the key goal of differentiating between healthy small fetuses and those that are small through fetal growth restriction. As abnormal placentation is thought to be the major cause of fetal growth restriction, one approach is to combine fetal biometry with an indicator of placental dysfunction. In the past, these indicators were generally ultrasonic measurements, such as Doppler flow velocimetry of the uteroplacental circulation. However, another promising approach is to combine ultrasonic suspicion of small-for-gestational-age infant with a blood test indicating placental dysfunction. Thus far, much of the research on maternal serum biomarkers for fetal growth restriction has involved the secondary analysis of tests performed for other indications, such as fetal aneuploidies. An exemplar of this is pregnancy-associated plasma protein A. This blood test is performed primarily to assess the risk of Down syndrome, but women with low first-trimester levels are now serially scanned in later pregnancy due to associations with placental causes of stillbirth, including fetal growth restriction. The development of "omic" technologies presents a huge opportunity to identify novel biomarkers for fetal growth restriction. The hope is that when such markers are measured alongside ultrasonic fetal biometry, the combination would have strong predictive power for fetal growth restriction and its related complications. However, a series of important methodological considerations in assessing the diagnostic effectiveness of new tests will have to be addressed. The challenge thereafter will be to identify novel disease-modifying interventions, which are the essential partner to an effective screening test to achieve clinically effective population-based screening.
Publisher: Elsevier BV
Date: 08-2009
DOI: 10.1016/J.CBI.2009.04.012
Abstract: Members of the ATP-binding cassette (ABC) family of membrane-bound transporters are involved in multiple aspects of transport and redistribution of various lipids and their conjugates. Most ABC transporters localize to the plasma membrane some are associated with liquid-ordered cholesterol-/sphingolipid-rich microdomains, and to a lesser extent the membranes of the Golgi and endoplasmic reticulum. Hence, ABC transporters are well placed to regulate plasma membrane lipid composition and the efflux and redistribution of structural phospholipids and sphingolipids during periods of cellular stress and recovery. ABC transporters can also modulate cellular sensitivity to extrinsic pro-apoptotic signals through regulation of sphingomyelin-ceramide biosynthesis and metabolism. The functionality of ABC transporters is, in turn, modulated by the lipid content of the microdomains in which they reside. Cholesterol, a major membrane microdomain component, is not only a substrate of several ABC transporters, but also regulates ABC activity through its effects on microdomain structure. Several important bioactive lipid mediators and toxic lipid metabolites are also effluxed by ABC transporters. In this review, the complex interactions between ABC transporters and their lipid/sterol substrates will be discussed and analyzed in the context of their relevance to cellular function, toxicity and apoptosis.
Publisher: Elsevier BV
Date: 09-2011
Publisher: Elsevier BV
Date: 10-2012
DOI: 10.1016/J.MCE.2012.05.009
Abstract: Sphingolipid mediators such as ceramide are pleiotropic regulators of cellular growth, differentiation and apoptosis. We investigated the role of ceramide biosynthesis, metabolism and actions in term human cytotrophoblasts syncytialized over 7 days in culture. Intracellular C16 ceramide levels increased modestly after 3 days in culture, then declined. Ceramidase was present at particularly high levels in syncytialized trophoblasts inhibition of ceramidase reduced the degree of cell fusion. Exposure to short chain C8 ceramide or aSMase enhanced secretion of the differentiation marker hCG without affecting fusion or cell viability. In contrast, pharmacological inhibition of ceramidase reduced the extent of fusion. Inhibition of the ceramide-responsive JNK and PP2A pathways did not abolish the effects of ceramide, and JNK phosphorylation was unresponsive to ceramide however, ceramide significantly inhibited phosphorylation of Akt. This study suggests that changes in ceramide biosynthesis and metabolism play a differential role in the biochemical and morphological features of trophoblast differentiation.
Publisher: Proceedings of the National Academy of Sciences
Date: 11-01-2016
Publisher: Elsevier BV
Date: 08-2007
DOI: 10.1016/J.PLACENTA.2007.03.001
Abstract: Placental ATP-binding cassette (ABC) transporters limit fetal exposure to xenobiotics by regulating transplacental passage into the fetal circulation their expression and function in fetal membranes, however, has not been studied. In the present study the expression, localisation and function of ABC transporters in human amnion was examined to explore their potential role in modulating amniotic fluid drug disposition in pregnancy. Single-assay oligo-microarrays were used to profile amnion gene expression, and drug transporters expressed at significant levels were identified and selected for further studies. The expression of ABCG2/breast cancer resistance protein (BCRP) and multidrug resistance-associated proteins (MRP) 1 (ABCC1), 2 (ABCC2) and 5 (ABCC5) was detected on the arrays, and verified by RT-PCR and immunoblotting. On confocal microscopy of fetal membrane cryosections, MRP1 and MRP5 were immunolocalised to both apical and basolateral surfaces of the amniotic epithelium, while MRP2 was expressed at low levels only in the apical membrane. BCRP in contrast showed cytoplasmic staining throughout the amniotic epithelium. In addition to the amnion, MRP1 and BCRP immunostaining was observed in the chorion and the decidua. Cell accumulation studies using selective MRP and BCRP inhibitors showed the transporters to be functionally active in amnion epithelial monolayer cultures. In contrast, transwell transport studies using intact amnion membranes did not show significant vectorial transport. These findings identify the amnion as a novel site of ABC drug transporter expression. Functional studies indicate that they may act primarily to prevent cellular xenobiotic accumulation, rather than to confer fetal protection through reduced accumulation in amniotic fluid.
Publisher: Elsevier BV
Date: 03-2011
Publisher: American Society for Clinical Investigation
Date: 12-07-2018
Publisher: Elsevier BV
Date: 11-2012
Publisher: Springer Science and Business Media LLC
Date: 09-06-2015
Publisher: Oxford University Press (OUP)
Date: 06-2014
Publisher: Elsevier BV
Date: 02-2012
DOI: 10.1016/J.RBMO.2011.10.012
Abstract: Sphingosine and sphingosine-1-phosphate (S1P) are involved in regulating cell differentiation. This study postulated that changes in sphingolipid biosynthesis and metabolism are important in trophoblast syncytialization and therefore examined the production, metabolism and actions of sphingosine and S1P during spontaneous trophoblast differentiation and fusion in vitro. Significant declines in intracellular sphingosine concentration (P≤0.05) and sphingosine kinase 1 (SPHK1) expression (P≤0.01) were observed during trophoblast syncytialization. Secreted S1P concentrations dropped steeply after 72h, before rising to basal concentrations with syncytialization. Intracellular S1P concentrations were undetectable throughout. Treating cells with exogenous sphingosine (P≤0.01), S1P (P≤0.001) or a specific SPHK1 inhibitor (P≤0.05) for up to 72h in culture significantly inhibited trophoblast differentiation (measured as reduced human chorionic gonadotrophin production) effects on other biochemical and morphological markers of differentiation were absent or inconsistent. Phosphorylation of Akt, an established down-stream target of S1P that spontaneously declines with trophoblast differentiation, was markedly reduced by S1P (P≤0.05). In conclusion, changes in the sphingosine-S1P pathway are involved in the regulation of trophoblast differentiation in term human placenta. Dysregulation of sphingolipid homeostasis could, therefore, disrupt placental formation and function with deleterious consequences for pregnancy outcome.
Publisher: Elsevier BV
Date: 03-2013
Publisher: Elsevier BV
Date: 12-2014
Publisher: Cold Spring Harbor Laboratory
Date: 11-03-2021
DOI: 10.1101/2021.03.10.432857
Abstract: In pregnancy, adiponectin serves as an endocrine link between maternal adipose tissue, placental function and fetal growth, with low adiponectin promoting placental function and fetal growth. Circulating adiponectin levels are decreased in obese pregnant women and in gestational diabetes, which is believed to contribute to the insulin resistance and increased risk of fetal overgrowth associated with these conditions. However, the molecular mechanisms governing adiponectin secretion from maternal adipose tissues in pregnancy are poorly understood. Using visceral adipose tissue from lean and obese pregnant mice, we show that obesity in pregnancy is associated with adipose tissue inflammation, ER stress, insulin resistance, increased adiponectin ubiquitination and decreased total abundance of adiponectin. Moreover, adiponectin ubiquitination was increased in visceral fat of obese pregnant women as compared to lean pregnant women. We further observed that insulin prevents, whereas ER stress and inflammation promote, adiponectin ubiquitination and degradation in differentiated 3T3-L1 adipocytes. We have identified key molecular pathways regulating adiponectin secretion in pregnancy. This information will help us better understand the mechanisms controlling maternal insulin resistance and fetal growth in pregnancy and may provide a foundation for the development of strategies aimed at improving adiponectin production in pregnant women with obesity or gestational diabetes.
Publisher: Cold Spring Harbor Laboratory
Date: 16-06-2018
DOI: 10.1101/348755
Abstract: Group 2 innate lymphoid cells (ILC2s) adapt to tissue physiology and contribute to immunity, inflammatory pathology and metabolism. We show that mouse uterine ILC2s have a heightened type-2 gene signature and expand during pregnancy. Indeed, maternal ILC2s promote fetal growth and protect against fetal mortality upon systemic endotoxin challenge. Absence of ILC2s leads to utero-placental abnormalities, including poor vascular remodelling, increased Il1b and decreased Il4, Il5 , and Il13 gene expression, and reduced alternative activation of dendritic cells (DCs) and macrophages. Placentas exhibit signs of adaptation to stress, including larger maternal blood spaces and increased expression of nutrient transporter genes. Endotoxin induces the expansion of IL-1β-producing uterine DCs and, in response, more uterine ILC2s produce IL-4, IL-5 and IL-13. In a protective feedback mechanism, these cytokines suppress IL-1β-producing DCs, in line with a protective role of uILC2s against endotoxin-induced abortion. Uterine ILC2s emerge as pivotal for both normal and complicated pregnancies.
Publisher: Elsevier BV
Date: 02-2011
DOI: 10.1016/J.PLACENTA.2010.12.007
Abstract: Oxygenated cholesterol metabolites known as oxysterols display potent biological activities ranging from regulation of lipid homeostasis to cytotoxicity. Oxysterols have previously been shown to inhibit the invasion of first trimester trophoblasts, an effect which involves activation of the nuclear liver X receptors (LXRs). In the present study, we investigated the effects of several oxysterols on syncytialisation (differentiation and fusion) in term placental trophoblasts. Treatment of cultured term primary trophoblast cells with oxysterols [25-hydroxycholesterol, 7-ketocholesterol, 22(R)-hydroxycholesterol] and the synthetic LXR agonist T0901317 at non-toxic doses decreased expression of GCM-1 and HERV-W mRNA and reduced hCG secretion and placental alkaline phosphatase activity, indicative of diminished trophoblast differentiation. Furthermore, treatment with these compounds also decreased cell fusion measured by E-cadherin immunostaining and quantification of syncytialised nuclei. Treatment with an LXR antagonist (geranylgeranyl diphosphate) abrogated the inhibitory effects of oxysterols and T0901317 on trophoblast syncytialisation indicating that these effects are mediated by LXR. These findings suggest that oxysterols impair differentiation and fusion of term trophoblast cells via an LXR-dependent mechanism.
Publisher: Springer Science and Business Media LLC
Date: 15-06-2022
DOI: 10.1038/S42003-022-03530-6
Abstract: Placental function and dysfunction differ by sex but the mechanisms are unknown. Here we show that sex differences in polyamine metabolism are associated with escape from X chromosome inactivation of the gene encoding spermine synthase (SMS). Female placental trophoblasts demonstrate biallelic SMS expression, associated with increased SMS mRNA and enzyme activity. Polyamine depletion in primary trophoblasts reduced glycolysis and oxidative phosphorylation resulting in decreased acetyl-coA availability and global histone hypoacetylation in a sex-dependent manner. Chromatin-immunoprecipitation sequencing and RNA-sequencing identifies progesterone biosynthesis as a target of polyamine regulated gene expression, and polyamine depletion reduced progesterone release in male trophoblasts. The effects of polyamine depletion can be attributed to spermine as SMS-silencing recapitulated the effects on energy metabolism, histone acetylation, and progesterone release. In summary, spermine metabolism alters trophoblast gene expression through acetyl-coA biosynthesis and histone acetylation, and SMS escape from X inactivation explains some features of human placental sex differences.
Publisher: Proceedings of the National Academy of Sciences
Date: 28-09-2015
Abstract: Obesity and metabolic syndrome may, in part, originate in fetal life. In particular, babies of mothers with obesity and/or gestational diabetes mellitus (GDM) are often large at birth and have increased adiposity, which predisposes them to the development of metabolic disease later in life. Maternal obesity and GDM are typically associated with low circulating levels of adiponectin (ADN), and we found that ADN supplementation to pregnant obese mice completely normalized the changes in placental function and prevented fetal overgrowth caused by maternal obesity. These findings suggest that strategies to increase ADN levels in maternal obesity and GDM may alleviate the adverse effects of these pregnancy complications on the fetus.
Publisher: Elsevier BV
Date: 02-2022
DOI: 10.1016/J.AJOG.2020.11.005
Abstract: The placenta is a highly metabolically active organ fulfilling the bioenergetic and biosynthetic needs to support its own rapid growth and that of the fetus. Placental metabolic dysfunction is a common occurrence in preecl sia although its causal relationship to the pathophysiology is unclear. At the outset, this may simply be seen as an "engine out of fuel." However, placental metabolism plays a vital role beyond energy production and is linked to physiological and developmental processes. In this review, we discuss the metabolic basis for placental dysfunction and propose that the alterations in energy metabolism may explain many of the placental phenotypes of preecl sia such as reduced placental and fetal growth, redox imbalance, oxidative stress, altered epigenetic and gene expression profiles, and the functional consequences of these aberrations. We propose that placental metabolic reprogramming reflects the dynamic physiological state allowing the tissue to adapt to developmental changes and respond to preecl sia stress, whereas the inability to reprogram placental metabolism may result in severe preecl sia phenotypes. Finally, we discuss common tested and novel therapeutic strategies for treating placental dysfunction in preecl sia and their impact on placental energy metabolism as possible explanations into their potential benefits or harm.
Publisher: Elsevier BV
Date: 09-2010
DOI: 10.1016/J.BBALIP.2010.05.015
Abstract: ATP-binding cassette (ABC) transporters ABCA1 and ABCG1 mediate the efflux of cholesterol and other sterols. Both transporters are expressed on the fetal capillaries of the placenta and are involved in maternal-to-fetal cholesterol delivery. In this study, we report that ABCA1 and ABCG1 are also present on the syncytiotrophoblast, the maternal facing placental membrane. Syncytial ABCA1 expression is apical, suggesting a role in cholesterol efflux to the mother, while ABCG1 is expressed basolaterally indicating transport to the fetus. Silencing of ABCA1 expression in primary trophoblasts in culture, or pharmacological antagonism by glyburide, decreased cholesterol efflux to apolipoprotein A-I (apoA-I) compared to controls, while ABCG1-silencing decreased cholesterol efflux to high density lipoproteins (HDL). In contrast, treatment with endogenous or synthetic LXR alpha/beta ligands such as T0901317 increased ABCA1 and ABCG1 expression and enhanced cholesterol efflux to apoA-I and HDL, respectively, while treatment with pharmacological PPAR-alpha or -gamma ligands was without effect. Trophoblasts transfected with ABCA1 or ABCG1 siRNA were more sensitive to toxic oxysterols substrates (25-hydroxycholesterol and 7-ketocholesterol) compared to mock-transfected cells, while prior treatment with T0901317 reduced oxysterol-mediated toxicity. These results identify syncytial ABCA1 and ABCG1 as important, inducible cholesterol transporters which also prevent placental accumulation of cytotoxic oxysterols.
Publisher: American Physiological Society
Date: 04-2023
DOI: 10.1152/AJPCELL.00581.2022
Abstract: Human trophoblast cultures provide powerful tools to model key processes of placental development. In vitro trophoblast studies to date have relied on commercial media that contains nonphysiological levels of nutrients, and the impact of these conditions on trophoblast metabolism and function is unknown. Here, we show that the physiological medium (Plasmax) with nutrient and metabolite concentrations recapitulating human plasma improves human trophoblast stem cell (hTSC) proliferation and differentiation compared with standard medium (DMEM-F12). hTSCs cultured in Plasmax-based medium also show altered glycolytic and mitochondrial metabolism, as well as reduced S-adenosylmethionine/S-adenosyl-homocysteine ratio compared with DMEM-F12-based medium. These findings demonstrate the importance of the nutritional environment for phenotyping cultured human trophoblasts.
Publisher: The Endocrine Society
Date: 04-2014
DOI: 10.1210/ME.2013-1401
Publisher: Elsevier BV
Date: 12-2013
Publisher: Wiley
Date: 10-2015
DOI: 10.14814/PHY2.12594
Location: United States of America
Location: United Kingdom of Great Britain and Northern Ireland
Start Date: 2022
End Date: 2027
Funder: Medical Research Council
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